FI83085C - Förfarande för framställning av terapeutiskt användbara pyridazo/1,2-a //1,2/diazepinderivat - Google Patents
Förfarande för framställning av terapeutiskt användbara pyridazo/1,2-a //1,2/diazepinderivat Download PDFInfo
- Publication number
- FI83085C FI83085C FI862805A FI862805A FI83085C FI 83085 C FI83085 C FI 83085C FI 862805 A FI862805 A FI 862805A FI 862805 A FI862805 A FI 862805A FI 83085 C FI83085 C FI 83085C
- Authority
- FI
- Finland
- Prior art keywords
- alkyl
- aralkyl
- formula
- compound
- pyridazo
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 45
- 238000002360 preparation method Methods 0.000 title claims description 7
- 125000002576 diazepinyl group Chemical class N1N=C(C=CC=C1)* 0.000 title 1
- -1 aralkoxyalkyl Chemical group 0.000 claims description 170
- 150000001875 compounds Chemical class 0.000 claims description 167
- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 100
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 82
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
- 239000001257 hydrogen Substances 0.000 claims description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004945 acylaminoalkyl group Chemical group 0.000 claims description 22
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 21
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 20
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 19
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical class N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000002253 acid Substances 0.000 description 42
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 239000000126 substance Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 22
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 22
- 230000008020 evaporation Effects 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 239000003960 organic solvent Substances 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 150000007942 carboxylates Chemical class 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 238000005886 esterification reaction Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 11
- 229910000085 borane Inorganic materials 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 230000032050 esterification Effects 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000007363 ring formation reaction Methods 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 5
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 5
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 229920001429 chelating resin Polymers 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- 229910000510 noble metal Inorganic materials 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- CRGRWBQSZSQVIE-UHFFFAOYSA-N diazomethylbenzene Chemical compound [N-]=[N+]=CC1=CC=CC=C1 CRGRWBQSZSQVIE-UHFFFAOYSA-N 0.000 description 4
- COSZWAUYIUYQBS-UHFFFAOYSA-B hexapotassium hexasodium 3-carboxy-3-hydroxypentanedioate 2-hydroxypropane-1,2,3-tricarboxylate hydrate Chemical compound O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[K+].[K+].[K+].[K+].[K+].[K+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O COSZWAUYIUYQBS-UHFFFAOYSA-B 0.000 description 4
- 229910000039 hydrogen halide Inorganic materials 0.000 description 4
- 239000012433 hydrogen halide Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
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- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
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- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 3
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- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
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- XKCQASMZNPBLKI-UHFFFAOYSA-N phosphorosooxymethane Chemical compound COP=O XKCQASMZNPBLKI-UHFFFAOYSA-N 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Claims (19)
1. Förfarande för framställning av pyridazo-[1,2-a][1,2]diazepinderivat med formeln (I) och farmaceu-5 tiskt godtagbara salter därav, _4 5 - „χΦ, " | 0 COOR OR2 där R1 är hydroxi, alkyl, aralkyl, aralkoxi-alkyl, hydr-15 oxi-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxikarbonylamino-alkyl, halogen-alkyl, karboxialkyl, alkoxikarbonyl-alkyl, alkoxi eller aralkoxi; R2 och R3 vardera är väte, alkyl eller aralkyl; R4 och R5 vardera är väte eller R4 och R5 till-20 sammans bildar en oxogrupp; och X är en syreatom eller en grupp -NR6-, där R6 är väte, alkyl eller aralkyl eller -(CH2)n, där n är 0, 1 eller 2, varvid alkyl- och alkoxi-grupperna innehäller 1-8 kolatomer, acyl betecknar acetyl, propionyl, butyryl, valeryl, cyklopropankarbonyl, 25 cyklopentankarbonyl, bensoyl, p-klorbensoyl, fenylacetyl eller nikotinoyl, och aralkyl och aralkoxi betecknar alkyl- eller alkoxigrupper, där en väteatom ersatts med fe-nyl, som eventuellt substituerats med en eller flera halogen-, alkyl-, alkoxi-, trifluormetyl-, nitro-, amino-30 eller iminoalkylaminogrupper, kännetecknat därav, att a) för framställning av en förening med formeln (I), där R1 är alkyl, aralkyl, aralkoxi-alkyl, acylamino-alkyl, dialkylamino-alkyl, alkoxikarbonylamino-alkyl, al-35 koxikarbonyl-alkyl, alkoxi eller aralkoxi, R2 och R3 bäda 67 83085 är alkyl eller aralkyl, R4 och R5 tlllsammans bildar en oxogrupp och X är -(CH2)n-, där n betecknar samma som ovan, omsätts en förenlng med den allmänna formeln Hal (CH2)n 0 COOR30 10 där n betecknar samma som ovan, R30 är alkyl eller aralkyl och Hai är en halogenatom, med en förenlng med den allmänna formeln 15 O-R20 R10-P (III) ^ O-R20 20 där R10 är alkyl, aralkyl, aralkoxi-alkyl, acylamino-al-kyl, dialkylamino-alkyl, alkoxikarbonylaminoalkyl, al-koxikarbonyl-alkyl, alkoxl eller aralkoxl och R20 är alkyl eller aralkyl, eller 25 b) för framställning av en förenlng med formeln (I), där R1 är alkyl, aralkyl, aralkoxi-alkyl, acylamino-alkyl, dialkylamino-alkyl, alkoxikarbonylamino-alkyl, al-koxikarbonyl-alkyl, alkoxi eller aralkoxl, R2 och R3 var-dera är alkyl eller aralkyl; och X är en syreatom eller 30 en grupp -NR6-, där R6 är väte, alkyl eller aralkyl, omsätts en förenlng med den allmänna formeln R, R5 GQ» H —X 0 COOR 68 83085 där R4, R5 och R1 2 3 4 5 6 betecknar samma som ovan och X1 är en syreatom eller en grupp -NR6-, där R6 betecknar samma som ovan, med en förening med den allmänna formeln 5 ,0 Ϊ R10— P-Hal (V) Ar20 10 där R10, R20 och Hai betecknar samma som ovan, eller c) för framställning av en förening med formeln (I), där R2 är alkyl eller aralkyl, R4 och R5 tillsammans bildar en oxogrupp och X är -CH2-, omsätts en förening med den allmänna formeln 15 O λ-rfV, 20 h2C 0 COOR där R3 betecknar samma som ovan, med en förening med den allmänna formeln 25
0-R7 Rl-P^^ (VII) O-R20 där R1 och R20 betecknar samma som ovan och R7 är alkyl, 2 aralkyl eller trialkylsilyl, eller 3 d) för framställning av en förening med formeln 4 (I), där R1 är alkyl, aralkyl, aralkoxi-alkyl, 5 aminoalkyl, acylaminoalkyl, monoalkylamino-alkyl, dial- 6 kylaminoalkyl, alkoxikarbonylamino-alkyl, alkoxikarbonyl- 69 83085 alkyl, alkoxl eller aralkoxi, R2 och R3 vardera fir alkyl eller aralkyl, och R4 och Rs vardera är väteatomer, reducer as en förening med formeln (I), där R1 är alkyl, aralkyl, aralkoxi-alkyl, amino-alkyl, acylamino-alkyl, mono-5 alkylaminoalkyl, dialkylamino-alkyl, alkoxikarbonylamino-alkyl, alkoxlkarbonyl-alkyl, alkoxl eller aralkoxi, R2 och R3 vardera är alkyl eller aralkyl, och R4 och R5 till-sanunans bildar en oxogrupp, eller e) för framställning av en förening med formeln 10 (I), där R1 är hydroxi, alkyl, aralkyl, aralkoxi-alkyl, hydroxi-alkyl, amino-alkyl, acylamino-alkyl, monoalkyl-amino-alkyl, dialkylamino-alkyl, alkoxikarbonylamino-al-kyl, halogen-alkyl, karboxialkyl, alkoxikarbonyl-alkyl, alkoxi eller aralkoxi, R2 är väte, alkyl eller aralkyl 15 och/eller R3 är väte, alkyl eller aralkyl, förutsatt, att antingen R1 är väte och/eller ätminstone den ena av R2 och R3 är väte, ändamälsänligt deesteriefieras en förening med formeln (I), där R1 är hydroxi, alkyl, aralkyl, araloxi-alkyl, hydroxi-alkyl, amino-alkyl, acylamino-al-20 kyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxikar-bonylamino-alkyl, halogen-alkyl, karboxi-alkyl, alkoxikarbonyl -alkyl, alkoxi eller aralkoxi, R2 är väte, alkyl eller aralkyl och/eller R3 är väte, alkyl eller aralkyl, förutsatt, att antingen R1 är annat än hydroxi och/eller 25 ätminstone den ena av R2 och R3 är annat än väte, eller f) för framställning av en förening med formeln (I), där R1 är alkyl, aralkyl, aralkoxi-alkyl, hydroxi-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxikarbonylamino-alkyl, halo- 30 gen-alkyl, karboxialkyl, alkoxikarbonylalkyl, alkoxi el ler aralkoxi, R2 är alkyl eller aralkyl och R3 är alkyl eller aralkyl, ändamälsenligt förestras en förening med formeln (I), där R1 är alkyl, aralkyl, aralkoxi-alkyl, hydroxi-alkyl, amino-alkyl, acylaminoalkyl, monoalkyl-35 amino-alkyl, dialkylamino-alkyl, alkoxikarbonylamino-al- 70 83085 kyl, halogen-alkyl, karboxl-alkyl, alkoxikarbonyl-alkyl, alkoxl eller aralkoxl, R2 är alkyl eller aralkyl och R3 är väte, eller g) för framställning av en förening med formeln 5 (I), där Rl är hydroxi-alkyl och R2 och R3 vardera är väte eller alkyl, katalytiskt hydreras en förening med formeln (I), där R1 är aralkoxl-alkyl och R2 och R3 vardera är väte eller alkyl, eller h) för framställning av en förening med formeln 10 (I), där R1 är amlnoalkyl eller monoalkylamlno-alkyl och R2 och R3 vardera är alkyl eller aralkyl, omvandlas hyd-roxi-alkylgruppen 1 en förening med formeln (I), där R1 är hydroxi-alkyl och R2 och R3 vardera är alkyl eller aralkyl, till en amino-alkyl- eller monoalkylamlno-alkyl-15 grupp, och 1. ifali önskvärt, reduceras en nitrosubstituerad fenylgrupp 1 R1 1 en förening med formeln (I) tili en aminosubstituerad fenylgrupp, och/eller j) ifall önskvärt, omvandlas en aminosubstituerad 20 fenylgrupp i R1 i en förening med formeln (I) tili en iminoalkylaminogrupp, genom omsättning av föreningen med formeln (I) med alkylcyanid 1 närvaro av trialkylsilylha-logenid, och/eller k) ifall önskvärt, uppdelas den erhällna bland- 25 ningen av diastereoisomeriska racemat i diastereoisome- riska racemat eller optiskt rena diastereoisomerer, och/-eller l) ifall önskvärt, uppdelas det erhällna racematet i optiskä antipoder, och 30 m) ifall önskvärt, omvandlas den erhällna före ningen med formeln (I) tili ett farmaceutiskt godtagbart sait.
2. Förfarande enligt patentkravet 1, känne-t e c k n a t därav, att föreningarna med formeln (I) 35 och farmaceutiskt godtagbara salter därav framställs en- 7i 83085 ligt utföringsforraer a), b), d), e), e) f), g), h), k), 1. eller m).
3. Förfarande enligt patentkravet 1 eller 2, kännetecknat därav, att R1 är hydroxl, alkyl, 5 aralkyl eller aralkoxi.
4. Förfarande enligt nägot av patentkraven 1-3, kännetecknat därav, att R2 är väte.
5. Förfarande enligt nägot av patentkraven 1-4, kännetecknat därav, att R3 är väte. 10
6. Förfarande enligt nägot av patentkraven 1-5, kännetecknat därav, att X är en syreatom eller en grupp -NH- eller -(CH2)n-, där n är 0 eller 1.
7. Förfarande enligt nägot av patentkraven 1-6, kännetecknat därav, att R1 är hydroxi, alkyl, 15 aralkyl eller alkoxi, R2 är väte, R3 är väte och X är en syreatom eller en grupp -NH- eller -(CH2)n, där n är 0 eller 1.
8. Förfarande enligt patentkravet 2, kännetecknat därav, att man framställer oktahydro-9(S)- 20 fosfonometyl-10-oxo-6H-pyridazo[l,2-a][1,2]diazepin-l(S)-karboxylsyra.
9. Förfarande enligt patentkravet 2, kännetecknat därav, att man framställer oktahydro-9(S)-[t(hydroxi)metylfosfinyl]metyl]-6,10-dioxo-6H-pyridazo- 25 [1,2-a][1,2]diazepin-l(S)-karboxylsyra.
10. Förfarande enligt patentkravet 2, kännetecknat därav, att man framställer oktahydro-9(S)-fosfono-6,10-dioxo-6H-pyridazo[l,2-a][1,2]diazepin-l(S)-karboxylsyra. 30
11. Förfarande enligt patentkravet 2, känne tecknat därav, att man framställer 9(S)-dietoxi-fosfinyloktahydro-6,10-dioxo-6H-pyridazo[l,2-a][1,2]di-azepin-1(S)-karboxylsyra.
12. Förfarande enligt patentkravet 2, k ä n n e - 35 tecknat därav, att man framställer oktahydro-9(S)- 72 83085 [[hydroxi(metoxi)fosfinyl]metyl]-6,10-dioxo-6H-pyridazo-[1,2-a][1,2]diazepin-l(S)-karboxylsyra.
13. Förfarande enligt patentkravet 2, k ä n nets c k n a t därav, att man framställer oktahydro-9(S)- 5 fosfonometyl-6,10-dioxo-6H-pyridazo[l,2-a][1,2]diazepin-1(S)-karboxylsyra.
14. Förfarande enligt patentkravet 2, känne-t e c k n a t därav, att man framställer 9(S)-[[hydroxi-(3-fenylpropyl)fosfinyl]metyl]-oktahydro-6,10-dioxo-6H- 10 pyridazo[l,2-a][1,2]diazepin-l(S)-karboxylsyra.
15. Förfarande enligt patentkravet 2, känne-t e c k n a t därav, att man framställer 9(S)-[[hydroxi-(fenetyl)fosfinyl]amino]-oktahydro-10-oxo-6H-pyridazo-[1,2-a][1,2]diazepin-l(S)-karboxylsyra. 15
16. Förfarande enligt patentkravet 1, känne- t e c k n a t därav, att man framställer 9(S)-[[hydroxi-(2-fenetyl)fosfinyl]metyl]-oktahydro-10-oxo-6H-pyridazo-[1,2-a][1,2]diazepin-l(S)-karboxylsyra.
17. Förfarande enligt patentkravet 1, känne- 20 tecknat därav, att man framställer 9(S)-[hydroxi- (4-fenylbutyl)fosfinyl]-oktahydro-10-oxo-6H-pyridazo[1,2- a][1,2]diazepin-l(S)-karboxylsyra.
18. Föreningar med den allmänna formeln 25 0 ¢0 .....
30 Hal—(CH2)2 0 coor30 där R30 är alkyl eller aralkyl och Hal är en halogenatom.
19. Föreningar med den allmänna formeln 35 73 83085 R, „5 tj_ o ' Il I 30 H 0 o COOR där R4 och R5 bäda Mr väte eller tillsammans bildar en 10 oxogrupp; och R30 Mr alkyl eller aralkyl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB858516604A GB8516604D0 (en) | 1985-07-01 | 1985-07-01 | Pyridazodiazepine derivatives |
| GB8516604 | 1985-07-01 | ||
| GB8609591 | 1986-04-18 | ||
| GB868609591A GB8609591D0 (en) | 1985-07-01 | 1986-04-18 | Pyridazodiazepine derivatives |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI862805A0 FI862805A0 (fi) | 1986-07-01 |
| FI862805A FI862805A (fi) | 1987-01-02 |
| FI83085B FI83085B (fi) | 1991-02-15 |
| FI83085C true FI83085C (sv) | 1991-05-27 |
Family
ID=26289446
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI862805A FI83085C (sv) | 1985-07-01 | 1986-07-01 | Förfarande för framställning av terapeutiskt användbara pyridazo/1,2-a //1,2/diazepinderivat |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4743687A (sv) |
| EP (1) | EP0211220A1 (sv) |
| AU (1) | AU592996B2 (sv) |
| CS (1) | CS489986A2 (sv) |
| DK (1) | DK297386A (sv) |
| ES (2) | ES8801264A1 (sv) |
| FI (1) | FI83085C (sv) |
| HU (2) | HU201302B (sv) |
| IL (1) | IL79234A0 (sv) |
| MC (1) | MC1755A1 (sv) |
| NZ (1) | NZ216630A (sv) |
| PT (1) | PT82886B (sv) |
| ZW (1) | ZW11586A1 (sv) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0334164B1 (de) * | 1988-03-24 | 1993-10-27 | F. Hoffmann-La Roche Ag | Antihypertensives Kombinationspräparat |
| US6417189B1 (en) | 1999-11-12 | 2002-07-09 | Gpi Nil Holdings, Inc. | AZA compounds, pharmaceutical compositions and methods of use |
| US7253169B2 (en) | 1999-11-12 | 2007-08-07 | Gliamed, Inc. | Aza compounds, pharmaceutical compositions and methods of use |
| KR101246685B1 (ko) * | 2010-09-10 | 2013-03-21 | 제일모직주식회사 | 난연성 폴리카보네이트 절연필름 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2716677C2 (de) * | 1977-04-15 | 1985-10-10 | Hoechst Ag, 6230 Frankfurt | Cephemderivate und Verfahren zu ihrer Herstellung |
| IL60617A0 (en) * | 1979-07-23 | 1980-09-16 | Sparamedica Ag | Triazolopyridazine derivative,their preparation and pharmaceutical compositions containing them |
| EP0025941B1 (de) * | 1979-09-19 | 1983-05-04 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyridazopyridazinderivate, Verfahren zu deren Herstellung und Arzneimittel enthaltend solche Pyridazopyridazinderivate |
| EP0042100A1 (de) * | 1980-06-13 | 1981-12-23 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyrazolopyridazin-Derivate, Zwischenprodukte und Verfahren zu deren Herstellung, sowie diese enthaltende Arzneimittel |
| GB2128984B (en) * | 1982-05-12 | 1985-05-22 | Hoffmann La Roche | Diaza-bicyclic compounds |
| US4692438A (en) * | 1984-08-24 | 1987-09-08 | Hoffmann-La Roche Inc. | Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activity |
-
1986
- 1986-06-04 ZW ZW115/86A patent/ZW11586A1/xx unknown
- 1986-06-23 NZ NZ216630A patent/NZ216630A/en unknown
- 1986-06-23 US US06/877,085 patent/US4743687A/en not_active Expired - Fee Related
- 1986-06-24 DK DK297386A patent/DK297386A/da not_active Application Discontinuation
- 1986-06-25 ES ES556590A patent/ES8801264A1/es not_active Expired
- 1986-06-25 IL IL79234A patent/IL79234A0/xx unknown
- 1986-06-25 AU AU59241/86A patent/AU592996B2/en not_active Ceased
- 1986-06-26 EP EP86108736A patent/EP0211220A1/de not_active Withdrawn
- 1986-06-27 HU HU891699A patent/HU201302B/hu not_active IP Right Cessation
- 1986-06-27 MC MC861840A patent/MC1755A1/xx unknown
- 1986-06-27 HU HU862699A patent/HU199859B/hu not_active IP Right Cessation
- 1986-06-30 CS CS864899A patent/CS489986A2/cs unknown
- 1986-07-01 PT PT82886A patent/PT82886B/pt not_active IP Right Cessation
- 1986-07-01 FI FI862805A patent/FI83085C/sv not_active IP Right Cessation
-
1987
- 1987-04-15 ES ES557503A patent/ES8900230A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| HUT42769A (en) | 1987-08-28 |
| ES8900230A1 (es) | 1989-04-16 |
| MC1755A1 (fr) | 1987-04-24 |
| AU592996B2 (en) | 1990-02-01 |
| FI83085B (fi) | 1991-02-15 |
| US4743687A (en) | 1988-05-10 |
| CS489986A2 (en) | 1991-02-12 |
| ES8801264A1 (es) | 1988-01-01 |
| AU5924186A (en) | 1987-01-08 |
| PT82886B (pt) | 1989-05-31 |
| NZ216630A (en) | 1990-04-26 |
| DK297386A (da) | 1987-01-02 |
| PT82886A (en) | 1986-08-01 |
| DK297386D0 (da) | 1986-06-24 |
| IL79234A0 (en) | 1986-09-30 |
| HU201302B (en) | 1990-10-28 |
| HU199859B (en) | 1990-03-28 |
| FI862805A0 (fi) | 1986-07-01 |
| ZW11586A1 (en) | 1987-12-30 |
| ES557503A0 (es) | 1989-04-16 |
| ES556590A0 (es) | 1988-01-01 |
| FI862805A (fi) | 1987-01-02 |
| EP0211220A1 (de) | 1987-02-25 |
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| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: F. HOFFMANN-LA ROCHE AG |